- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03661385
Nitric Oxide During Bypass for Arterial Switch Operation (NASO)
A Randomised Controlled Trial of Nitric Oxide Administration During Cardiopulmonary Bypass in Infants Undergoing Arterial Switch Operation for Repair of Transposition of the Great Arteries
This trial will test if adding nitric oxide (NO) gas to the cardiopulmonary bypass (CPB) circuit in infants undergoing an arterial switch operation (ASO) for Transposition of the Great Arteries (TGA) changes the incidence of major postoperative adverse events (AEs).
Major postoperative AEs include cardiac arrest, emergency chest opening, use of ECMO (machine that acts as an artificial heart and lung during surgery), and death.
Participants will be randomised to receive oxygen plus nitric oxide (intervention arm) or oxygen without nitric oxide (control arm) during CPB.
Study Overview
Status
Intervention / Treatment
Detailed Description
The incidence of congenital heart disease (CHD) is approximately 1/100 live born children, of which up to 50% require cardiac surgery to correct the underlying abnormality at some stage during their life. (Centre for Disease Control and Prevention, USA). Despite major improvements in CPB devices, the exposure of host blood to large artificial organ surfaces, combined with myocardial injury during planned myocardial ischemia, results in a significant systemic inflammatory response. CPB-triggered systemic inflammatory syndrome is responsible for the most serious and potentially life-threatening side effects associated with cardiac surgery. It is characterized by endotoxin release, leukocyte and complement activation, and widespread activation of inflammatory mediators, resulting in endothelial leak, increased oxygen consumption, and organ dysfunction.
NO is an endogenous anti-inflammatory mediator that helps to protect endothelial beds and immunologically active cells. NO has a myocardial protective effect by reducing reperfusion injury. NO generation is essential for regulation of endothelial function and microvascular inflammation. However, dysregulation of endogenous NO during CPB may aggravate the subsequent inflammatory response.
A randomized controlled study adding NO into the bypass circuit was conducted by the Royal Children's Hospital in Melbourne on 198 children. This pilot study confirmed the positive effects of gaseous NO reported in the U.S. trial, as well as a reduction in the incidence of low cardiac output syndrome (LCOS). Other improved patient outcomes included a reduced need for extracorporeal life support (ECLS), trends towards a reduced length of stay, and shorter duration of ventilation. In light of these promising preliminary results from these two separate studies, a large multicentre trial to test these findings in children requiring cardiac surgery is needed.
The NASO study is running concurrently with the Nitric Oxide during Cardio Pulmonary Bypass during surgery for congenital heart defects: A Randomised Controlled Trial study (ANZCTR Trial Registry ID: ACTRN12617000821392) within Australia (run by Lady Cilento, Brisbane). This study is aiming to look at the effects of Nitric Oxide on all children under the age of 2 years undergoing bypass surgery for CHD.
TGA presents in 5-7% of all patients with congenital heart disease and isolated TGA is managed in a similar manner all over the world. The surgical treatment for this is the ASO. Hence this single operation and diagnosis provides an appropriate setting to evaluate the efficacy of NO in the CPB circuit. By allowing each centre to have their own protocols of care (pre, intra and postoperatively) and only collecting 'routine clinical data", the investigators anticipate each centre having high rates of screening and consent.
Patients will be stratified by centre and by age at time of surgery. Participants will be randomized into one of two arms:
- Intervention arm will receive NO 20 parts per million (ppm) into the oxygenator of a cardio-pulmonary bypass circuit
- Control arm will not receive NO
At the end of CPB, the participants will return to the Intensive Care Unit where normal care will continue.
A total of 800 participants will be enrolled in the study and will be stratified by centre and age at time of surgery.
Study aims to investigate whether exposure to gaseous NO reduces the incidence of postoperative major adverse events in infants on cardiopulmonary bypass.
Study Type
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Contact
- Name: Kate L Masterson, Research Nurse PICU
- Phone Number: 56492 +61 3 93455522
- Email: kate.masterson@rch.org.au
Study Contact Backup
- Name: Warwick Butt, Prof
- Email: warwick.butt@rch.org.au
Study Locations
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Victoria
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Melbourne, Victoria, Australia, 3050
- Royal Children's Hospital
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Alberta
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Edmonton, Alberta, Canada, AB T6G 2B7
- Stollery Cildren's Hospital
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Jakarta, Indonesia
- Harapan Kita Children and Women's Hospital
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Kuala Lumpur, Malaysia, 50400
- Institut Jantung Negara
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion criteria;
Each participant must meet all of the following criteria to be enrolled in this study:
- Infant aged greater than or equal to 36 weeks gestation
- Infants less than 2 years
- Diagnosed with TGA and requiring Arterial Switch Operation
- Consent of parents/guardian.
Exclusion criteria
Potential participants will be excluded if they meet any of the following criteria:
- They have multiple major congenital anomalies (anomalies which affect the infant's life expectancy or health status)
- They have multiple other cardiac abnormalities (with the exception of ASD, VSD or PDA)
- They weigh less than 2.2kgs.
- Prior surgical exposure to cardio-pulmonary bypass
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Prevention
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: Intervention arm
• Intervention arm will receive nitric oxide 20 parts per million (ppm) into the oxygenator of a cardio-pulmonary bypass circuit
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Addition of nitric oxide 20ppm into bypass circuit
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No Intervention: Control arm
Control arm will not receive nitric oxide, they will receive standard bypass as per local policy
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Major adverse events
Time Frame: 28 days post intervention
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The primary outcome is the number of participants with major adverse events (MAEs) within 28 days post-operatively.
MAEs include cardiac arrest, emergency chest opening, use of ECMO, and death.
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28 days post intervention
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Length of stay in ICU (hours)
Time Frame: This will be calculated from date and time of admission to ICU to date and time of discharge from ICU in hours up to 28 days
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Length of stay in ICU (hours) will be calculated from date and time of admission to ICU date and time of discharge to ICU.
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This will be calculated from date and time of admission to ICU to date and time of discharge from ICU in hours up to 28 days
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Length of stay in hospital (days)
Time Frame: 28 days (or until hospital discharge)
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Length of stay in hospital (days) will be calculated from date and time of admission to hospital to date and time of discharge to hospital.
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28 days (or until hospital discharge)
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Ventilator-free days
Time Frame: 28 days (or until ICU discharge)
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Ventilator-free days will be calculated from date and time of intubation to date and time of extubation.
Each day (or part of a day) will be counted as a day.
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28 days (or until ICU discharge)
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Inotrope hours
Time Frame: Number of hours inotropes have been administered during first 28 days post operatively
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Inotrope hours will be calculated from data input into REDCAP.
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Number of hours inotropes have been administered during first 28 days post operatively
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Dialysis-free days
Time Frame: 28 days (or until ICU discharge)
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Dialysis-free days will be calculated from date and time of start of dialysis to date and time of stopping dialysis.
Each day (or part of a day) will be counted as a day.
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28 days (or until ICU discharge)
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Inhaled NO hours
Time Frame: Number of hours inhaled NO have been administered during first 28 days post operatively
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Inhaled NO hours will be calculated from data input into REDCAP.
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Number of hours inhaled NO have been administered during first 28 days post operatively
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ECMO-free days
Time Frame: 28 days (or until ICU discharge)
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ECMO-free days will be calculated from date and time of start of ECMO to date and time of stopping ECMO.
Each day (or part of a day) will be counted as a day.
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28 days (or until ICU discharge)
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Closed sternum days
Time Frame: 28 days (or until ICU discharge)
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Closed sternum days will be calculated from date and time of start of chest opening (or return to ICU time if delayed chest closure) to date and time of chest closure.
Each day (or part of a day) will be counted as a day.
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28 days (or until ICU discharge)
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Composite free-day score
Time Frame: 28 days (or until hospital discharge)
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This score is a combination of scores 1-8 to create a composite free-day score.
Composite free-day score is a score highlighting the number of days free from post-operative complications including free of hospitalization within the first 28 days post operatively.
For each score, the days free of complication will be calculated to create an individual free from score these will be then added together to create an overall free-from score.
Higher scores suggest a better outcome (free from hospital and complications).
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28 days (or until hospital discharge)
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Collaborators and Investigators
Investigators
- Principal Investigator: Warwick Butt, MRCI
Publications and helpful links
General Publications
- Levy JH, Tanaka KA. Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg. 2003 Feb;75(2):S715-20. doi: 10.1016/s0003-4975(02)04701-x.
- Chello M, Mastroroberto P, Perticone F, Celi V, Colonna A. Nitric oxide modulation of neutrophil-endothelium interaction: difference between arterial and venous coronary bypass grafts. J Am Coll Cardiol. 1998 Mar 15;31(4):823-6. doi: 10.1016/s0735-1097(97)00560-3.
- Hataishi R, Rodrigues AC, Neilan TG, Morgan JG, Buys E, Shiva S, Tambouret R, Jassal DS, Raher MJ, Furutani E, Ichinose F, Gladwin MT, Rosenzweig A, Zapol WM, Picard MH, Bloch KD, Scherrer-Crosbie M. Inhaled nitric oxide decreases infarction size and improves left ventricular function in a murine model of myocardial ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol. 2006 Jul;291(1):H379-84. doi: 10.1152/ajpheart.01172.2005. Epub 2006 Jan 27.
- Zahler S, Massoudy P, Hartl H, Hahnel C, Meisner H, Becker BF. Acute cardiac inflammatory responses to postischemic reperfusion during cardiopulmonary bypass. Cardiovasc Res. 1999 Mar;41(3):722-30. doi: 10.1016/s0008-6363(98)00229-6.
- Checchia PA, Bronicki RA, Muenzer JT, Dixon D, Raithel S, Gandhi SK, Huddleston CB. Nitric oxide delivery during cardiopulmonary bypass reduces postoperative morbidity in children--a randomized trial. J Thorac Cardiovasc Surg. 2013 Sep;146(3):530-6. doi: 10.1016/j.jtcvs.2012.09.100. Epub 2012 Dec 8.
- James C, Millar J, Horton S, Brizard C, Molesworth C, Butt W. Nitric oxide administration during paediatric cardiopulmonary bypass: a randomised controlled trial. Intensive Care Med. 2016 Nov;42(11):1744-1752. doi: 10.1007/s00134-016-4420-6. Epub 2016 Sep 30.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Heart Diseases
- Cardiovascular Diseases
- Congenital Abnormalities
- Heart Defects, Congenital
- Cardiovascular Abnormalities
- Transposition of Great Vessels
- Cardiac Output, Low
- Situs Inversus
- Physiological Effects of Drugs
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Vasodilator Agents
- Autonomic Agents
- Peripheral Nervous System Agents
- Protective Agents
- Bronchodilator Agents
- Anti-Asthmatic Agents
- Respiratory System Agents
- Antioxidants
- Free Radical Scavengers
- Endothelium-Dependent Relaxing Factors
- Gasotransmitters
- Nitric Oxide
Other Study ID Numbers
- 38017
- ACTRN12618000089235p (Registry Identifier: ANZCTR)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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